A novel biallelic variant c.2219T > A p.(Leu740*) in ADGRG6 as a cause of lethal congenital contracture syndrome 9

Adhesion G protein-coupled receptor G6 (ADGRG6) is a major con-stituent of the basement membrane essential for normal myelination of axons. To date, variants in ADGRG6 are known to be associated with lethal congenital contracture syndrome 9 (LCCS9; MIM#616503) in three published reports comprising of six families and additionally, two families with intellectual disability and joint contractures. 1 – 5 Here, we describe an additional Asian family with a novel variant in ADGRG6 as a cause of LCCS9.

A consanguineous couple had an intrauterine fetal demise at 24 weeks of gestation following preeclampsia in their first conception.In the second pregnancy, ultrasonography at 18 weeks of gestation showed a short and curved left thumb, flexion deformity at the left wrist, and early onset of intrauterine fetal growth restriction.At 32 weeks of gestation polyhydramnios was noted.The family history was unremarkable.The informed consent for the study was obtained.The perinatal assessment was done following stillbirth.The female fetus weighed 1404 g (−0.957SD), measured 33 cm (−4.2 SD) in length, and had a head circumference of 32 cm (+1.82 SD).Clinical information noted in the fetus is described in Table 1.Skeletal survey and microscopic evaluation of the biceps, femoral nerve, and diaphragm were normal.
Chromosomal microarray from fetal DNA was normal.Trioexome sequencing (TWIST Biosciences) identified, a novel stop-gain biallelic variant c.2219 T > A p.(Leu740*) in exon 15 of ADGRG6 in the proband.Parents are heterozygous for the variant and are healthy.This variant is not observed in any individual in the gnomAD database and our in-house database of 1683 exomes.In-silico prediction tools predict this variant results in nonsense-mediated mRNA decay or in the formation of non-functional protein.The variant is classified to be pathogenic according to the ACMG guidelines.
The clinical features associated with LCCS9 are facial dysmorphism, pulmonary hypoplasia, and arthrogryposis, which are in concordance with our family. 2,3Notably, the Iranian family presented with intellectual disability, speech impairment, microcephaly, seizures, cerebellar hypoplasia, and spasticity with join contractures. 3Two siblings from other family had intellectual disability, optic atrophy, agenesis of corpus callosum, sensorimotor neuropathy, joint contractures, and cardiac valve anomaly along with biallelic variants in one more locus (C12ORF65), thus explaining some features (Table 1). 5Gpr126 is required for the normal ear development in zebrafish and in the heart, spine, and body length/mass development in mice. 1,6Adolescent idiopathic scoliosis has been associated with Gpr126 in mice earlier. 6PR126 modulates angiogenesis through VEGF signaling and is important in cardiovascular development in mice and zebrafish. 7It is also known that variants in ADGRG6/GPR126 are linked to breast and bladder cancers in humans. 6e GPR126, consists of signal peptide (SP), Complement C1r/C1s, Uegf and Bmp1 (CUB), Pentraxin (PTX), GPCR autoproteolysis-inducing (GAIN), and a C-terminal 7 transmembrane (7TM) domains.The GAIN domain is conserved and mediates an autocatalytic cleavage crucial for activating GPCR126 signaling. 1,3All individuals (2/9 families) with variants (missense and truncating) in the GAIN domain are observed with neonatal deaths. 1 Similarly, we also report a stillbirth with a biallelic stop-gain variant in the GAIN domain.Notably, few individuals (family with a missense variant in the 7TM domain and other family with a missense variant between PTX and GAIN domain) are with less severe phenotype or non-lethal and are alive up to adolescence with intellectual disability (Table 1). 2-5However, we do not know the reason behind the varying severity of the phenotype.In addition, we could not establish an association between the type of variant, effect on protein, and the severity of phenotype.A greater number of families will provide further insights.
To conclude, the phenotype of ADGRG6-related disorders ranges from lethal arthrogryposis in fetuses to intellectual disability and joint contractures in adults.Our study delineates an additional family with LCCS9 and further explores the reported families.

Table 1 Clinical and molecular profile of individuals assessed in the present and previous studies Ravenscroft et al. 1 Laquerriere et al. 2 Hosseini et al. 3 Daum et al. 4 Karaca et al. 5 Present study Family 1 Individual 1 Family 2 Individual 1 Family 3 Family 4 Individual 1 Family 5 Individual 1 Family 6 Family 7 Individual 1 Family 8 a Family 9 Individual 1 Individual 1 Individual 2 Individual 1 Individual 2 Individual 1 Individual 2
Clin Genet.Author manuscript; available in PMC 2024 August 22.